1. Field of the Invention
The present invention relates to an MS/MS type mass spectrometer which splits ions having a specific mass-to-charge ratio (m/z) by collision-induced dissociation (CID) and performs mass spectrometry on the product ions (fragment ions) produced as a result.
2. Description of the Background Art
One known method of performing mass spectrometry in order to identify or analyze the structure of a substance with a large molecular weight is MS/MS analysis (also called tandem analysis). A typical MS/MS mass spectrometer is a triple quadrupole (TQ) type mass spectrometer. FIG. 12 is a schematic configuration diagram of a general triple quadrupole type mass spectrometer disclosed in Patent Literature 1 or the like.
This mass spectrometer is provided with an ion source 2 for ionizing a sample to be analyzed, three levels of quadrupoles 3, 5, and 6, each consisting of four rod electrodes, and a detector 7 for detecting ions and outputting a detection signal corresponding to the amount of ions inside an analysis chamber 1 which is vacuum-pumped by a vacuum pump not shown in the drawing. A voltage combining a direct-current voltage and a high-frequency voltage is applied to the first quadrupole 3, and only target ions having a prescribed mass-to-charge ratio are selected as precursor ions from among various ions produced by the ion source 2 due to the action of an electric field generated as a result of this voltage.
The second quadrupole 5 is housed inside a collision cell 4 with a high degree of air-tightness. A CID gas such as argon (Ar), for example, is introduced into this collision cell 4. The precursor ions sent from the first quadrupole 3 to the second quadrupole 5 collide with the CID gas inside the collision cell 4, which causes splitting due to collision-induced dissociation and produces product ions. There are various forms of this splitting, so a plurality of types of product ions with different mass-to-charge ratios are normally produced from precursor ions of one type. These various product ions exit the collision cell 4 and are introduced into the third quadrupole 6. Ordinarily, only a high-frequency voltage is applied or a voltage generated by adding a direct-current bias voltage to a high-frequency voltage is applied to the second quadrupole 5, and this second quadrupole 5 functions as an ion guide for transporting ions to the next level while converging the ions.
As in the case of the first quadrupole 3, a voltage combining a direct-current voltage and a high-frequency voltage is applied to the third quadrupole 6. Only product ions having a specific mass-to-charge ratio are selected by the third quadrupole 6 so as to reach the detector 7 due to an electric field generated as a result of this voltage. By appropriately changing the direct-current voltage and the high-frequency voltage applied to the third quadrupole 6, it is possible to scan the mass-to-charge ratios of ions which may pass through the third quadrupole 6 (product ion scan). In this case, a data processing part not shown in the drawing can create a mass spectrum (MS/MS spectrum) of product ions generated by the splitting of the target ions based on a detection signal obtained by the detector 7. In addition, it is also possible to execute a precursor ion scan to search for all precursor ions producing specific product ions or a neutral loss scan to search for all precursor ions for which a specific partial structure has been lost.
In an LC/MS/MS or GC/MS/MS device using the MS/MS type mass spectrometer described above as a detector for liquid chromatography (LC) or gas chromatography (GC), a technique called MRM (Multiple Reaction Monitoring) is often used to perform simultaneous analysis (identification and assay) of multiple components contained in a sample. In MRM measurements, product ions having a specific one or a plurality of mass-to-charge ratios are selected by the third quadrupole 6 in a state in which the mass-to-charge ratio of precursor ions selected by the first quadrupole 3 is fixed, and the signal strength of these product ions is measured. Since the plurality of components contained in the sample separate over time in LC or GC, it is possible to find the signal strength of ions derived from each component with high precision and high sensitivity by changing the mass-to-charge ratios of the precursor ions and the product ions in accordance with the elution time (retention time) of each component.
In MRM measurements, the detection of a pair of one given precursor ion and one given product ion is performed successively as time passes, but significant data cannot be obtained at the time of the switching of the mass-to-charge ratios. Therefore, as shown in FIGS. 13 and 14, a suspension time of an appropriate length is set between the data collection for a given pair of a precursor ion and a product ion and the next pair of a precursor ion and a product ion. FIGS. 13 and 14 are drawings which schematically show the changes in ionic strength over time due to the remaining ions in the collision cell 4.
In a mass spectrometer with the configuration described above, a CID gas is fed into the collision cell 4, so the gas pressure inside the collision cell 4 is typically higher at approximately mTorr than the gas pressure outside the collision cell 4. When ions advance through a high-frequency electric field in an atmosphere with such a comparatively high gas pressure, the kinetic energy of the ions is attenuated and the speed of the ions decreases due to collision with the gas.
In MRM measurements, if the speed of advancement of ions decreases in the collision cell 4 as described above, when the mass-to-charge ratio of the precursor ions is switched from a given value M1 to another value M2, ions of the previous mass-to-charge ratio M1 and product ions derived from these ions still remain in the collision cell 4 in spite of the introduction of ions of the switched mass-to-charge ratio M2 into the collision cell 4 having been started, and there is a risk that these ions may mix. This is a phenomenon called crosstalk in MS/MS analysis, and when there is crosstalk, the assay properties and the like of the target component are diminished.
Therefore, in the mass spectrometer described in Patent Literature 2, a pulse voltage is applied to the lens electrode on the inlet side or the outlet side of the collision cell 4 in the suspension period during which the mass-to-charge ratio of the precursor ions is switched, and ions are attracted to and made to collide with the lens electrode due to the action of an electric field formed temporarily inside the collision cell as a result of the pulse voltage. As a result, it is possible to remove from within the collision cell 4 precursor ions with the previous mass-to-charge ratio and the product ions derived from the precursor ions before the precursor ions with the switched mass-to-charge ratio are introduced into the collision cell 4, which makes it possible to avoid crosstalk.
However, when a pulse voltage for ion removal is applied to the lens electrode in a state in which a large amount of ions remain in the collision cell 4, the amount of ions colliding with the lens electrode becomes large, and the contamination of the lens voltage worsens. In order to minimize this contamination, in the device described in Patent Literature 2, a pulse voltage for ion removal is applied to the lens electrode with a delay of a prescribed amount of time from the starting point of the suspension period. That is, as shown in FIGS. 13 and 14, a pulse voltage with a pulse width of p (=t4−t3) is applied to the lens electrode at a point t3 when a prescribed delay time d has passed from a point t1 when the suspension period was begun. During the delay time d, the ions in the collision cell 4 are discharged little by little to the outside. Therefore, the amount of ions remaining inside the collision cell 4 is reduced at the point t3 when the pulse voltage is applied, and there are few collisions between the ions and the lens electrode when the pulse voltage is applied, which makes it possible to reduce the contamination of the lens electrode.
As described above, data based on the detection signal of the detector 7 is not collected during the suspension period, and the collection of data is resumed at the termination point t2 of the suspension period. Therefore, the suspension period is wasted time in the measurements, and it is preferable for the suspension time to be shorter in order to improve the throughput of the measurements. In addition, when the sample components change with the passing of time, as in the case of LC/MS/MS or GC/MS/MS, it is preferable for the suspension time to be shorter in order to prevent the missed detection of components. However, a short suspension time leads to the following such problems.
Specifically, as shown in FIG. 13, after a pulse voltage is applied during the suspension period so that practically all of the ions remaining in the collision cell are temporarily removed, the product ions derived from the next precursor ions begin to accumulate in the collision cell 4, so the amount of ions in the collision cell 4 gradually rises from the termination point t4 of the application of the pulse voltage. Only when these ions pass through the third quadrupole 6 and reach the detector 7 can an ionic strength based on the product ions derived from the precursor ions after the switching of the mass-to-charge ratio be obtained. Therefore, the rise of the detected ionic strength takes a certain amount of time, and if the suspension period is too short, the amount of ions incident on the detector 7 may not have yet sufficiently recovered at the starting point t2 of the detection period for collecting data next. In such a situation, the measurement sensitivity decreases in the initial stages of the detection period.
On the other hand, if the amount of ions remaining in the collision cell 4 is too large at the point t1 when the suspension period is begun, as shown in FIG. 14, the remaining ions are not completely removed (the strength does not reach zero) during the period in which the pulse voltage is applied to the lens electrode, and the product ions derived from the next precursor ions begin to accumulate while some ions still remain. In such a situation, it becomes impossible to completely eliminate crosstalk.